Isoxazolopyridine type mevalonolactones

ABSTRACT

The present invention provides a compound of the formula: ##STR1## process for their production, pharmaceutical compositions containing them and their pharmaceutical uses, and intermediates useful for their production and processes for the production of such intermediates. The compounds are used as anti-hyperlipoproteinemic agents for example.

The present invention relates to novel mevalonolactones having aisoxazolopyridine ring, processes for their production, pharmaceuticalcompositions containing them and their pharmaceutical uses particularlyas hypolipoproteinemic and anti-atherosclerotic agents, andintermediates useful for their production and processes for theproduction of such intermediates.

Some fermentation metabolic products such as compactin, CS-514,Mevinolin or semi-synthetic derivatives or fully synthetic derivativesthereof are known to be inhibitors against HMG-CoA reductase which is arate limiting enzyme for cholesterol biosynthesis. (A. Endo J. MedChem., 28(4) 401 (1985)).

CS-514 and Mevinolin have been clinically proved to be potentiallyuseful anti-hyperlipoproteinemic agents, and they are considered to beeffective for curing or preventing diseases of coronary arteriosclerosisor atherosclerosis. (IXth Int. Symp. Drugs Affect. Lipid Metab., 1986,Abstract, p30, p31, p60).

However, with respect to fully synthetic derivatives, particularlyhetero aromatic derivatives of inhibitors against HMG-CoA reductase,limited information is disclosed in the following literatures:

WPI ACC Nos. 84-158675, 86-028274, 86-098816, 86-332070, 87-124519,87-220987, 88-007781, 88-008460, 88-091798, 88-112505, 88-182950,88-234828, 88-258359, 88-265052, 88-280597, 88-300969, 89-15672,89-24911, 89-24913, 89-25270, 89-25474, 89-48221, 89-78429.

The present inventors have found that mevalonolactone derivatives havinga isoxazolopyridine ring, which has not been known, the correspondingdihydroxy carboxylic acids and salts and esters thereof have highinhibitory activities against cholesterol biosynthesis wherein HMG-CoAreductase acts as a rate limiting enzyme. The present invention has beenaccomplished on the basis of this discovery.

The novel mevalonolactone derivatives of the present invention arerepresented by the following formula I: ##STR2## wherein R¹ is hydrogen,C₁₋₈ alkyl, C₂₋₆ alkenyl, C₃₋₇ cycloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio,fluoro, chloro, bromo, ##STR3## (wherein R⁵, R⁶ and R⁷ are independentlyhydrogen, C₁₋₄ alkyl, C₁₋₃ alkoxy, C₃₋₇ cycloalkyl, trifluoromethyl,fluoro, chloro or bromo), 2-, 3- or 4-pyridyl, 2- or 3-thienyl, 2- or3-furyl, 2- or 5-pyrimidyl, ##STR4## (wherein R⁵ is as defined above) or--NR⁸ R⁹ (wherein R⁸ and R⁹ are independently hydrogen, C₁₋₄ alkyl or##STR5## (wherein R⁵ is as defined above, and m is 1, 2 or 3) or R⁸ andR⁹ together form --(CH₂)_(j) -- (wherein j is 3, 4 or 5)); or C₁₋₃ alkylsubstituted by ##STR6## (wherein R⁵¹ is as defined above) and by 0, 1 or2 members selected from the group consisting of C₁₋₈ alkyl, or α-orβ-naphthyl; R² is hydrogen, C₁₋₈ alkyl, C₂₋₆ alkenyl, C₃₋₇ Cycloalkyl,C₅₋₇ cycloalkenyl or ##STR7## (wherein R⁵ is as defined above), or C₁₋₃alkyl substituted by ##STR8## (wherein R⁵, R⁶ and R⁷ are as definedabove) and by 0, 1 or 2 members selected from the group consisting ofC₁₋₃ alkyl; R³ and R⁴ are independently hydrogen, C₁₋₈ alkyl, C₃₋₇cycloalkyl, C₁₋₃ alkoxy, n-butoxy, i-butoxy, sec-butoxy, t-butoxy, R²³R²⁴ N-- (R²³ and R²⁴ are independently hydrogen or C₁₋₃ alkyl),trifluromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro,bromo, phenyl, phenoxy, benzyloxy, hydroxy, trimethylsilyloxy,diphenyl-t-butylsilyloxy, hydroxymethyl or --O(CH₂)_(l) OR¹⁰ (whereinR¹⁰ is hydrogen, or C₁₋₃ alkyl, and l is 1, 2 or 3); or when located atthe ortho position to each other, R³ and R⁴ may together form--CH═CH--CH═CH-- or methylenedioxy; Y is --CH₂ --, --CH₂ CH₂ --,--CH═CH--, --CH₂ --, --CH═CH , CH═CH--CH₂ --, --C(CH₃)═CH-- or--CH═C(CH₃)--; and Z is --Q--CH₂ WCH₂ --CO₂ R¹², ##STR9## (wherein Q is--C(O)--, --C(OR¹³)₂ -- or --CH(OH)--; W is --C(O)--, --C(OR¹³)₂ -- or--C(R¹¹)(OH)--; R¹¹ is hydrogen or C₁₋₃ alkyl; R¹² is hydrogen, R¹⁴(wherein R¹⁴ is alkyl moiety of chemically or physiologicallyhydrolyzable alkyl ester or M (wherein M is NHR¹⁷ R¹⁸ R¹⁹ (wherein R¹⁷,R¹⁸ and R¹⁹ are independently hydrogen or C₁₋₄ alkyl), sodium, potassiumor 1/2 calcium); two R¹³ are independently primary or secondary C₁₋₆alkyl; or two R¹³ together form --(CH₂)₂ -- or (CH₂)₃ --; and R¹⁵ andR¹⁶ are independently hydrogen or C₁₋₃ alkyl; or R¹⁵ and R¹⁶ togetherform --(CH₂)₂ -- or --(CH₂)₃ --).

Various substituents in the formula I will be described in detail withreference to specific examples. However, it should be understood thatthe present invention is by no means restricted by such specificexamples.

C₁₋₈ alkyl for R¹, R², R³ and R⁴ includes, for example, methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl,1,2-dimethylpentyl, n-hexyl, n-heptyl and n-octyl.

C₁₄ alkyl for R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁷, R¹⁸ and R¹⁹ includes, forexample, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyland t-butyl.

C₁₋₃ alkyl for R¹⁰ R¹¹, R¹⁵, R¹⁶, R²³ and R²⁴ includes, for example,methyl, ethyl, n-propyl and i-propyl.

When R¹² is alkyl, R¹⁴ includes methyl, ethyl, n-propyl, i-propyl,c-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl (amyl),i-pentyl and n-hexyl.

C₁₋₆ alkyl for R¹³ includes, for example, methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, sec-butyl, n-pentyl and n-hexyl.

C₃₋₇ cycloalkyl for R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ includes, for example,cyclopropyl, 1-methylcyclopropyl, -methylcyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, 4-methylcyclohexyl and cycloheptyl.

C₁₋₆ alkoxy for R¹ includes, for example, methoxy, ethoxy, n-propoxy, ipropoxy, n-butoxy, i-butoxy, sec-butoxy, n-pentyloxy and n-hexyloxy.

C₁₋₃ alkoxy for R³, R⁴, R⁵, R⁶ and R⁷ includes, for example, methoxy,ethoxy, n-propoxy and i-propoxy.

C₁₋₆ alkylthio for R¹ includes, for example, methylthio, ethylthio,i-propylthio and n-hexylthio.

C₂₋₆ alkenyl for R¹ and R² includes, for example, vinyl, 1-methylvinyl,1-propenyl, allyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl,2-methyl-2-propenyl, 1-methyl-2-butenyl, 1-ethylvinyl,1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl,1-ethyl-2-propenyl, 1-methyl-1-butenyl, 1-methyl-2-butenyl,2-methyl-1-butenyl, 1-i-propylvinyl and 1-methyl-1-pentenyl.

C₅₋₇ cycloalkenyl for R² includes, for example, 2-cyclopentenyl,2-cyclohexenyl, 2-cycloheptenyl and 4-methyl-2-cyclohexenyl.

M is a metal capable of forming a pharmaceutically acceptable salt andincludes, for example, sodium, potassium and 1/2 calcium. CO₂ Mincludes, for example, --CO₂ NH₄ and --CO₂ H.(primary to tertiary loweralkylamine, for example, triethylamine).

Further, these compounds may have at least one or two asymmetric carbonatoms and may have at least two to four optical isomers. The compoundsof the formula I include all of these optical isomers and all of themixtures thereof.

Among compounds having carboxylic acid moieties falling outside thedefinition of --CO₂ R¹² of the carboxylic acid moiety of substitutent Zof the compounds of the present invention, those which undergophysiological hydrolysis, after intake, to produce the correspondingcarboxylic acids (compounds wherein the --CO₂ R¹² moiety is --CO₂ H) areequivalent to the compounds of the present invention.

Now, preferred substitutents of the compounds of the present inventionwill be described.

In the following preferred, more preferred, still further preferred andmost preferred examples, the numerals for the positions of thesubstituents indicate the positions on the isoxazolopyridine ring.

Preferred compound (1) of the formula I is a compound wherein R¹ ishydrogen, C₁₋₈ alkyl, C₂₋₆ alkenyl, C₃₋₇ Cycloalkyl, C₁₋₆ alkoxy,fluoro, chloro, bromo, ##STR10## (wherein R⁵, R⁶ and R⁷ areindependently hydrogen, C₁₋₄ alkyl, C₁₋₃ alkoxy, C₃₋₇ cycloalkyl,trifluoromethyl, fluoro, chloro or bromo), 2-, 3- or 4-pyridyl, 2- or3-thienyl, 2- or 3-furyl, 2- or 5-pyrimidyl or ##STR11## (wherein R⁵ isas defined above), or C₁₋₃ alkyl substituted by ##STR12## (wherein R⁵ isas defined above) and by 0, 1 or 2 members selected from the groupconsisting of C₁₋₈ alkyl, or α-or β-naphthyl; R² is hydrogen, C₁₋₈alkyl, C₂₋₆ alkenyl, C₃₋₇ cycloalkyl; R³ and R⁴ are independentlyhydrogen, C₁₋₈ alkyl, C₁₋₃ alkoxy, n-butoxy, i-butoxy, sec-butoxy,t-butoxy, trifluoromethyl, fluoro, chloro, bromo, phenoxy, benzyloxy,hydroxy, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl or--O(CH₂)_(l) OR¹⁰ (wherein R¹⁰ is hydrogen, or C₁₋₃ alkyl, and l is 1, 2or 3); or when located at the ortho position to each other, R³ and R⁴may together form methylenedioxy; Y is --CH₂ CH₂ -- or --CH═CH--; and Zis --Q--CH₂ WCH₂ --CO₂ R¹², ##STR13## (wherein Q is --C(O)-- or--CH(OH)--; W is --C(O)-- or --C(OH)--; and R¹² is as defined in claim1.

More preferred compound (2) of the formula I is a compound wherein R¹ ishydrogen, C₁₋₈ alkyl, C₂₋₆ alkenyl, C₃₋₇ cycloalkyl, ##STR14## (whereinR⁵, R⁶ and R⁷ are independently hydrogen, C₁₋₄ alkyl, C₁₋₃ alkoxy, C₃₋₇cycloalkyl, trifluoromethyl, fluoro, chloro or bromo), 2-, 3- or4-pyridyl, 2- or 3-thienyl, 2- or 3-furyl, or 2- or 5-pyrimidyl; or C₁₋₃alkyl substituted by ##STR15## (wherein R⁵ is as defined above) and by0, 1 or 2 members selected from the group consisting of C₁₋₈ alkyl, orα-or β-naphthyl; R² is primary or secondary C₁₋₄ alkyl or C₃₋₆cycloalkyl; R³ and R⁴ are as defined with respect to the compound (1)and located at the 3- and 4-position; Y is --CH₂ CH₂ -- or (E)--CH═CH--;and Z is as defined with respect to the compound (1).

Still further preferred compound (3) of the formula I is a compoundwherein R¹ is hydrogen, C₁₋₈ alkyl, C₂₋₆ alkenyl, C₃₋₇ cycloalkyl,##STR16## (wherein R⁵, R⁶ and R⁷ are independently hydrogen, C₁₋₄ alkyl,C₁₋₃ alkoxy, C₃₋₇ cycloalkyl, trifluoromethyl, fluoro, chloro or bromo);or C₁₋₃ alkyl substituted by ##STR17## (wherein R⁵ is as defined above)and by 0, 1 or 2 members selected from the group consisting of C₁₋₈alkyl; R² is ethyl, n-propyl, i-propyl or cyclopropyl; R³ and R⁴ areindependently hydrogen, C₁₋₈ alkyl, fluoro, chloro or bromo, and theyare located at the 3- and 4-position; and Y and Z are as defined withrespect to the compound (2).

The most preferred compound (4) is a compound wherein R¹ is hydrogen,methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, i-butyl, t-butyl,n-hexyl, n-octyl, vinyl, isopropenyl, cyclopropyl, cyclohexyl, phenyl,2-toluyl, 3-toluyl, 4-toluyl, 2-chlorophenyl, 3-chlorophenyl,4-chlorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl,3-trifluoromethylphenyl, 3,4-dichlorophenyl, 3,4-dimethylphenyl,3,4-dimethoxyphenyl, benzyl, α-methylbenzyl, 4-chlorobenzyl or4-methoxybenzyl; R² is i-propyl or cyclopropyl; when R⁴ is hydrogen, R³is hydrogen, 3-methyl, 4-methyl, 3-chloro, 4-chloro, 3-fluoro or4-fluoro; or R³ and R⁴ together form 3-methyl-4-chloro, 3,5-dichloro,3,5-difluoro, 3,5-dimethyl or 3-methyl-4-fluoro; and Y and Z are asdefined with respect to the compound (2).

Now, particularly preferred specific compounds of the present inventionwill be presented.

(a)(E)-7-[4'-(4"-fluorophenyl-3'-methyl-6'-(1"-methylethyl)isoxazolo[5,4-b]pyridin-5'-yl]-3,5-dihydroxyhept-6-enoicacid, a sodium salt, methyl ester, ethyl ester, n-propyl ester ori-propyl ester of the carboxylic acid, or a lactone formed by thecondensation of the carboxylic acid with hydroxy at the 5-position (b)(E)-7-[4'-(4"-fluorophenyl)-6'-(1"-methylethyl)-3'-phenylisoxazolo[5,4-b]pyridin-5'-yl]-3,5-dihydroxyhept-6-enoicacid, a sodium salt, methyl ester, ethyl ester, n-propyl ester ori-propyl ester of the carboxylic acid, or a lactone formed by thecondensation of the carboxylic acid with the hydroxy at the 5-position

The mevalonolactones of the formula I can be prepared by the followingscheme. ##STR18##

In the above reaction scheme, R¹, R², R³, R⁴ and R¹⁴ are as definedabove with respect to the formula I, and R²¹ and R²² independentlyrepresent C_(l-4) lower alkyl such as methyl, ethyl, n-propyl, i-propylor n-butyl.

The compound of the formula VII can be prepared by oxidizing thecompound of the formula X obtained by reacting the compound of theformula XI with the compound of the formula XII (Japanese UnexaminedPatent Publication No. 152386/1984).

Step A represents a reduction reaction of the ester to a primaryalcohol. Such reduction reaction can be conducted by using various metalhydrides, preferably diisobutylaluminium hydride, in a solvent such astetrahydrofuran, toluene or methylene chloride at a temperature of from-20° to 20° C., preferably from -10° to 10° C.

Step B represents an oxidation reaction of the primary alcohol to analdehyde, which can be conducted by using various oxidizing agents.Preferably, the reaction can be conducted by using pyridiniumchlorochromate in methylene chloride at a temperature of from 0° to 25°C., or by using oxalyl chloride, dimethyl sulfoxide and a tertiary aminesuch as triethylamine (Swern oxidation), or by using a sulfur trioxidepyridine complex.

Step C represents a synthesis of a 3-ethoxy-1-hydroxy-2-propenederivative, which can be prepared by reacting a compound V to a lithiumcompound which has been preliminarily formed by treatingcis-1-ethoxy-2-(tri-n-butylstannyl)ethylene with butyl lithium intetrahydrofuran.

As the reaction temperature, it is preferred to employ a low temperatureat a level of from -60° to -78° C.

Step D represents a synthesis of an enal by acidic hydrolysis. As theacid catalyst, it is preferred to employ p-toluenesulfonic acid,hydrochloric acid or sulfuric acid, and the reaction may be conducted ina solvent mixture of water and tetrahydrofuran or ethanol at atemperature of from 10° to 25° C. The 3-ethoxy-1-hydroxy-2-propenederivative obtained in Step C can be used in Step D without purificationi.e. by simply removing tetra-n-butyl tin formed simultaneously.

Step E represents a double anion addition reaction between the enal IIIand an acetoacetate. Such addition reaction is preferably conducted byusing sodium hydride and n-butyl lithium as the base in tetrahydrofuranat a temperature of from -80° to 0° C., preferably from -30° to -10° C.

Step F represents a reduction reaction of the ketocarboxylate of theformula II, by various reducing agents. This reaction comprisesreduction of carbonyl by e.g. sodium borohydride, sodiumcyanoborohydride, zinc borohydride, disiamylborane, diborane,t-butylaminoborane, pyridine-borane complex, dicyclohexylborane,thexylborane, 9- borabicyclo[3.3.1]nonane, diisopinocamphenyl borane orlithium tri-sec-butyl borohydride to the correspondingdihydroxycarboxylate of the formula I-1.

This reaction can be conducted in a solvent selected from hydrocarbons,halogenated hydrocarbons, C₁₋₄ alcohols, ethers and solvent mixturesthereof, at a temperature of from -100° to 50° C., preferably from -78°to 30° C.

Further, as described in J. Amer. Chem. Soc., 105, 593 (1983), atrialkylborane such as tri-n-butylborane or triethylborane and sodiumborohydride are used at a low temperature. Further, as described inTetrahedron Letters, 28, 155 (1987), the erythro form havingbiologically superior activities can advantageously be obtained by usingan alkoxydialkylborane such as methoxydiethylborane orethoxydiethylborane and sodium borohydride.

This reaction can be conducted by using a solvent mixture of C₁₋₄alcohol and tetrahydrofuran at a temperature of from -80° to -50° C.,preferably from -72° to -68° C.

Step G is a step for hydrolyzing the ester. The hydrolysis can beconducted by using an equimolar amount of a base, preferably potassiumhydroxide or sodium hydroxide, in a solvent mixture of water andmethanol or ethanol at a temperature of from 10° to 25° C. The free acidhereby obtained may be converted to a salt with a suitable base.

Step H is a step for forming a mevalonolactone by the dehydrationreaction of the free hydroxy acid I-2. The dehydration reaction can beconducted in benzene or toluene under reflux while removing theresulting water or by adding a suitable dehydrating agent such asmolecular sieve.

Further, the dehydration reaction may be conducted in dry methylenechloride by using a lactone-forming agent such as carbodiimide,preferably a water soluble carbodiimide such asN-cyclohexyl-N'-[2'-(methylmorpholinium)ethyl]carbodiimide p-toluenesulfonate at a temperature of from 10° to 35° C., preferably from 20° to25° C.

Step J represents a reaction for hydrogenating the double bondconnecting the mevalonolactone moiety and the isoxazolopyridine ring.This hydrogenation reaction can be conducted by using a catalytic amountof palladium-carbon or rhodium-carbon in a solvent such as methanol,ethanol, tetrahydrofuran or acetonitrile at a temperature of from 0° to50° C., preferably from 10° to 25° C.

Step K represents a reaction for the synthesis of an α,-β-unsaturatedcarboxylic acid ester, whereby a transform α,β-unsaturated carboxylicacid ester can be obtained by a so-called Horner-Wittig reaction byusing an alkoxycarbonylmethyl phosphonate. The reaction is conducted byusing sodium hydride or potassium t-butoxide as the base in drytetrahydrofuran at a temperature of from -30° to 0° C., preferably from-20° to -15° C.

Step L represents a reduction reaction of the α,β-unsaturated carboxylicacid ester to an allyl alcohol. This reduction reaction can be conductedby using various metal hydrides, preferably diisobutylaluminum hydride,in a solvent such as dry tetrahydrofuran or toluene at a temperature offrom -10° to 10° C., preferably from -10° to 0° C.

Step M represents an oxidation reaction of the allyl alcohol to an enal.This oxidation reaction can be conducted by using various oxidizingagents, particularly activated manganese dioxide, in a solvent such astetrahydrofuran, acetone, ethyl ether or ethyl acetate at a temperatureof from 0° to 100° C., preferably from 15° to 50° C., or in accordancewith so-called Swern oxidation by using oxalyl chloride,dimethylsulfoxide and a tertiary amine such as triethylamine.

Step N represents a reaction for the synthesis of an α,β-unsaturatedketone by the selective oxidation of the dihydroxy carboxylic acidester. This reaction can be conducted by using activated manganesedioxide in a solvent such as ethyl ether, tetrahydrofuran, benzene ortoluene at a temperature of from 20° to 80° C., preferably from 40° to80° C.

Further, the compound of the formula I-6 can be prepared from thealdehyde of the formula V by Wadsworth-Emmons coupling reaction (J.Amer. Chem. Soc., 107, 3731 (1985)). It can also be prepared from theenal of the formula III (Tetrahedron Letters, 26, 2951 (1985)).

Further, the compound of the formula I-7 can be prepared by adding adouble anion of an acetoacetate to the aldehyde of the formula XIIIprepared by the continuous Wittig reaction (WO-8402131) from thealdehyde of the formula V in the same manner as in Step E, to obtain theketocarbaoxylate of the formula XIV, and reducing the carbonyl group inthe same manner as in Step F.

Step AA represents a reduction reaction of the ketocarboxylate of theformula I-6 or XV by various reducing agents. This reaction comprisesreduction of carbonyl by e.g. sodium borohydride, sodiumcyanoborohydride, zinc borohydride, disiamylborane, diborane,t-butylaminoborane, pyridine-borane complex, dicyclohexylborane,thexylborane, 9-borabicyclo[3.3.1]nonane, diisopinocamphenyl borane orlithium tri-sec-butyl borohydride to the correspondingdihydroxycarboxylate of the formula I-1.

This reaction can be conducted in a solvent selected from hydrocarbons,halogenated hydrocarbons, C₁₋₄ alcohols, ethers and solvent mixturesthereof, at a temperature of from -100° to 50° C., preferably from -78°to 30° C.

Further, as described in J. Amer. Chem. Soc., 105, 593 (1983), atrialkylborane such as tri-n-butylborane or triethylborane and sodiumborohydride are used at a low temperature. Further, as described inTetrahedron Letters, 28, 155 (1987), the erythro form havingbiologically superior activities can advantageously be obtained by usingan alkoxydialkylborane such as methoxydiethylborane orethoxydiethylborane and sodium borohydride.

This reaction can be conducted by using a solvent mixture of Cl₁₋₄alcohol and tetrahydrofuran at a temperature of from -80° to -50° C.,preferably from -72° to -68° C.

Step BB represents a reaction of reducing the carbonyl group of theketocarboxylate of the formula XVI or XVII by using various reducingagent to obtain the corresponding dihydroxycarboxylate of the formulaI-7. This reaction can be conducted in the same manner as in Step AA.

Substituents R¹, R², R³ and R⁴ in from the compound of the formula VIwhich is an intermediate material of the phosphonium compound of theformula XVIII used in Steps CC-1, DD-1, EE-1 and the like, to thecompounds of the formula XX, XXII and XXIV, are those defined withrespect to the formula I excluding substituents having hydroxyl, aminoand monoalkylamino.

Steps CC 1 and CC-2 comprise reacting the compound of the formula XIXwith the compound of the formula XIII (wherein Hal is chlorine, bromineor iodine) by Wittig reaction to obtain the compound of the formula XX,(Step CC-1), followed by hydrolysis of the hydroxyl-protecting group(R²⁰) of the compound XX in the presence of a catalyst to obtain thecompound of the formula I-1 (Step CC-2).

The phosphonium compound of the formula XVIII can be obtained byhalogenating the hydroxyl group of the hydroxymethyl at the 5-positionof the isoxazolopyridine ring of the compound of the formula VI by ausual method, and then, reacting triphenylphosphine therewith.

The reactions of Steps CC-1 and CC-2 can be conducted in accordance withthe method disclosed in Tetrahedron Letters, 25, 2435 (1984), U.S. Pat.No. 4,650,890, EP No. 0 244 364, etc.

Wittig reaction can be conducted in a dry inert solvent. As the inertsolvent, an aliphatic hydrocarbon, toluene or an ether type solvent maybe mentioned. Preferred is the ether type solvent, such as diethylether, 1,2-diethoxyethane, 1,2-dimethoxyethane or tetrahydrofuran.

Wittig reaction can be conducted in a usual manner. A strong base isadded to a solution of the phosphonium compound of the formula XVIIIwithin a temperature range which does not affect the substituents of thephoshonium compound, to form the corresponding ylide compound, and then,the aldehyde of the formula XIX is added to the solution to form thedesired compound.

As examples of the strong base, sodium hydride and n-butyl lithium maybe mentioned, and preferred is n-butyl lithium.

The temperature upon the addition of the strong base is from -40° to 25°C., and the temperature upon the addition of the aldehyde is -35° to 30°C.

The hydroxyl-protecting group (R²⁰) of the compound of the formula XIX,XX, XXI, XXII, XXIII or XXIV is tri-substituted silyl, preferablydiphenyl-t-butylsilyl, which is usually used as a hydroxyl-protectinggroup. Preferred is a protecting group which can be removed withoutdecomposition of the ester or the lactone. The solvent used for theremoval. of the protecting group is an inert solvent such astetrahydrofuran or methanol. The catalyst used for the removal of theprotecting group is one commonly used for the reaction for removal ofsilyl. For example, a mixture of acetic acid and tetrabutylammoniumfluoride in tetrahydrofuran, or hydrochloride in methanol, may bementioned.

The reaction temperature for the removal of the protecting group is from20° to 60° C., preferably from 20° to 30° C.

When there are hydroxyl-protecting groups other than R²⁰ at the time ofthe removal of the protecting group, such protecting groups may beremoved to form hydroxyls.

Steps DD-1 to DD-3 represent Wittig reaction of the compound of theformula XVIII with the compound of the formula XXI (Step DD-1), followedby hydrolysis of the acetal to form the hemiacetal, by oxidation of thehemiacetal to form the lactone (Step DD-2), and then, by removal of thehydroxyl-protecting group (R²⁰) (Step DD-3).

The hydroxyl-protecting group (R²⁰) is as defined in Steps CC-1 andCC-2.

The reaction condition for Step DD-1 may be the same as in the method ofStep CC-1.

Step DD-2 represents (1) the hydrolysis and (2) the oxidation. Thehydrolysis can be conducted in a solvent mixture such as 10% HCl intetrahydrofuran or acetic acid/water/tetrahydrofuran, preferably aceticacid/water/tetrahydrofuran.

The reaction temperature is from 10° to 100° C., preferably from 20° to60° C.

The oxidation of the hemiacetal formed by the hydrolysis can beconducted under a mild condition. The reaction condition variesdepending upon the type of the oxidizing agent used.

When the oxidizing agent is pyridinium chlorochromate, the reactiontemperature is from 20° to 30° C., and the solvent used is halogenatedhydrocarbons, preferably methylene chloride.

Swern oxidation is conducted by using a mixture system of oxalylchloride/dimethylsulfoxide/triethylamine as the oxidizing agent, thereaction temperature is from -60° to -40° C., and the solvent used is ahalogenated hydrocarbon, preferably methylene chloride.

When the oxidizing agent is N-methylmorpholinoxide anddichloro-tris((phenyl)₃ P)-ruthenium II, the reaction temperature isfrom 0° to 40° C., preferably from 20° to 30° C., and the solvent is drydimethylformamide or acetone.

When the oxidizing agent is AgCO₃ on Celite, the reaction temperature isfrom 0° C. to the boiling point of the reaction solution, preferably atmost 150° C., and the solvent is benzene, toluene, xylene, etc.

The reaction condition for the removal of the protecting group in StepDD-3 may be the same as in the method of Step CC-2.

Steps EE-1 and EE-2 represent Wittig reaction of the compound of theformula XVIII with the compound of the formula XXIII (Step EE-1)followed by removal of the hydroxyl-protecting group (R²⁰) (Step EE-2).

The hydroxyl-protecting group (R²⁰) is as defined in Steps CC-1 andCC-2.

The reaction condition for the Step EE-1 may be the same as in themethod of Step CC-1.

The reaction condition for removing the protecting group in Step EE-2may be the same as in the method of Step CC-2.

The compounds of the formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8,I-9, II, XIV and XVI shown in Table 1, are typical examples of thecompounds of the present invention.

In Table 1, and in the following description, n- means normal, i- meansiso, sec- means secondary, t- means tertiary and c- means cyclo.Likewise, Me means methyl, Et means ethyl, Pr means propyl, Bu meansbutyl, Pent means pentyl, Hex means hexyl and Ph means phenyl.

                  TABLE 1                                                         ______________________________________                                         ##STR19##                                                                    ______________________________________                                        Compound    Y Z                                                               ______________________________________                                        (I-1) (R.sup.12 = Et)                                                                      ##STR20##                                                        (I-2) (R.sup.12 = H)                                                                       ##STR21##                                                        (I-3)                                                                                      ##STR22##                                                        (I-4)                                                                                      ##STR23##                                                        (I-5) (R.sup.12 = Na)                                                                      ##STR24##                                                        (I-6) (R.sup.12 = Et)                                                                      ##STR25##                                                        (I-7) (R.sup.12 = Et)                                                                      ##STR26##                                                        (I-8) (R.sup.12 = H)                                                                       ##STR27##                                                        (I-9) (R.sup.12 = Na)                                                                      ##STR28##                                                        (II) (R.sup.12 = Et)                                                                       ##STR29##                                                        (XIV) (R.sup.12 = Et)                                                                      ##STR30##                                                        (XVI) (R.sup.12 = Et)                                                                      ##STR31##                                                        ______________________________________                                        R.sup.1  R.sup.2     R.sup.3          R.sup.4                                 ______________________________________                                        H        i-Pr        4-F              H                                       H        i-Pr        4-F              3-Me                                    H        i-Pr        4-Cl             H                                       H        i-Pr        H                H                                       H        c-Pr        4-F              H                                       H        c-Pr        4-F              3-Me                                    H        c-Pr        4-Cl             H                                       H        c-Pr        H                H                                       Me       i-Pr        4-F              H                                       Me       i-Pr        4-F              3-Me                                    Me       i-Pr        4-Cl             H                                       Me       i-Pr        H                H                                       Me       c-Pr        4-F              H                                       Me       c-Pr        4-F              3-Me                                    Me       c-Pr        4-Cl             H                                       Me       c-Pr        H                H                                       Et       i-Pr        4-F              H                                       Et       i-Pr        4-F              3-Me                                    Et       i-Pr        4-Cl             H                                       Et       i-Pr        H                H                                       Et       c-Pr        4-F              H                                       Et       c-Pr        4-F              3-Me                                    Et       c-Pr        4-Cl             H                                       Et       c-Pr        H                H                                       i-Pr     i-Pr        4-F              H                                       i-Pr     i-Pr        4-F              3-Me                                    i-Pr     i-Pr        4-Cl             H                                       i-Pr     i-Pr        H                H                                       i-Pr     c-Pr        4-F              H                                       i-Pr     c-Pr        4-F              3-Me                                    i-Pr     c-Pr        4-Cl             H                                       i-Pr     c-Pr        H                H                                       n-Bu     i-Pr        4-F              H                                       n-Bu     i-Pr        4-F              3-Me                                    n-Bu     i-Pr        4-Cl             H                                       n-Bu     i-Pr        H                H                                       n-Bu     c-Pr        4-F              H                                       n-Bu     c-Pr        4-F              3-Me                                    n-Bu     c-Pr        4-Cl             H                                       n-Bu     c-Pr        H                H                                       c-Hex    i-Pr        4-F              H                                       c-Hex    i-Pr        4-F              3-Me                                    c-Hex    i-Pr        4-Cl             H                                       c-Hex    i-Pr        H                H                                       c-Hex    c-Pr        4-F              H                                       c-Hex    c-Pr        4-F              3-Me                                    c-Hex    c-Pr        4-Cl             H                                       c-Hex    c-Pr        H                H                                       Ph       i-Pr        4-F              H                                       Ph       i-Pr        4-F              3-Me                                    Ph       i-Pr        4-Cl             H                                       Ph       i-Pr        H                H                                       Ph       c-Pr        4-F              H                                       Ph       c-Pr        4-F              3-Me                                    Ph       c-Pr        4-Cl             H                                       Ph       c-Pr        H                H                                       PhCH.sub.2                                                                             i-Pr        4-F              H                                       PhCH.sub.2                                                                             i-Pr        4-F              3-Me                                    PhCH.sub.2                                                                             i-Pr        4-Cl             H                                       PhCH.sub.2                                                                             i-Pr        H                H                                       PhCH.sub.2                                                                             c-Pr        4-F              H                                       PhCH.sub.2                                                                             c-Pr        4-F              3-Me                                    PhCH.sub.2                                                                             c-Pr        4-Cl             H                                       PhCH.sub.2                                                                             c-Pr        H                H                                       3-pyridyl                                                                              i-Pr        4-F              H                                       3-pyridyl                                                                              i-Pr        4-F              3-Me                                    3-pyridyl                                                                              i-Pr        4-Cl             H                                       3-pyridyl                                                                              i-Pr        H                H                                       3-pyridyl                                                                              c-Pr        4-F              H                                       3-pyridyl                                                                              c-Pr        4-F              3-Me                                    3-pyridyl                                                                              c-Pr        4-Cl             H                                       3-pyridyl                                                                              c-Pr        H                H                                       4-ClPh   i-Pr        4-F              H                                       4-ClPh   i-Pr        4-F              3-Me                                    4-ClPh   i-Pr        4-Cl             H                                       4-ClPh   i-Pr        H                H                                       4-ClPh   c-Pr        4-F              H                                       4-ClPh   c-Pr        4-F              3-Me                                    4-ClPh   c-Pr        4-Cl             H                                       4-ClPh   c-Pr        H                H                                       4-MeOPh  i-Pr        4-F              H                                       4-MeOPh  i-Pr        4-F              3-Me                                    4-MeOPh  i-Pr        4-Cl             H                                       4-MeOPh  i-Pr        H                H                                       4-MeOPh  c-Pr        4-F              H                                       4-MeOPh  c-Pr        4-F              3-Me                                    4-MeOPh  c-Pr        4-Cl             H                                       4-MeOPh  c-Pr        H                H                                       4-MePh   i-Pr        4-F              H                                       4-MePh   i-Pr        4-F              3-Me                                    4-MePh   i-Pr        4-Cl             H                                       4-MePh   i-Pr        H                H                                       4-MePh   c-Pr        4-F              H                                       4-MePh   c-Pr        4-F              3-Me                                    4-MePh   c-Pr        4-Cl             H                                       4-MePh   c-Pr        H                H                                       n-octyl  i-Pr        4-F              H                                       n-octyl  i-Pr        4-F              3-Me                                    n-octyl  i-Pr        4-Cl             H                                       n-octyl  i-Pr        H                H                                       n-octyl  c-Pr        4-F              H                                       n-octyl  c-Pr        4-F              3-Me                                    n-octyl  c-Pr        4-Cl             H                                       n-octyl  c-Pr        H                H                                       Vinyl    i-Pr        4-F              H                                       Vinyl    i-Pr        4-F              3-Me                                    Vinyl    i-Pr        4-Cl             H                                       Vinyl    i-Pr        H                H                                       Vinyl    c-Pr        4-F              H                                       Vinyl    c-Pr        4-F              3-Me                                    Vinyl    c-Pr        4-Cl             H                                       Vinyl    c-Pr        H                H                                       c-Pr     i-Pr        4-F              H                                       c-Pr     i-Pr        4-F              3-Me                                    c-Pr     i-Pr        4-Cl             H                                       c-Pr     i-Pr        H                H                                       c-Pr     c-Pr        4-F              H                                       c-Pr     c-Pr        4-F              3-Me                                    c-Pr     c-Pr        4-Cl             H                                       c-Pr     c-Pr        H                H                                       MeO      i-Pr        4-F              H                                       MeO      i-Pr        4-F              3-Me                                    MeO      i-Pr        4-Cl             H                                       MeO      i-Pr        H                H                                       MeO      c-Pr        4-F              H                                       MeO      c-Pr        4-F              3-Me                                    MeO      c-Pr        4-Cl             H                                       MeO      c-Pr        H                H                                       MeS      i-Pr        4-F              H                                       MeS      i-Pr        4-F              3-Me                                    MeS      i-Pr        4-Cl             H                                       MeS      i-Pr        H                H                                       MeS      c-Pr        4-F              H                                       MeS      c-Pr        4-F              3-Me                                    MeS      c-Pr        4-Cl             H                                       MeS      c-Pr        H                H                                       Cl       i-Pr        4-F              H                                       Cl       i-Pr        4-F              3-Me                                    Cl       i-Pr        4-Cl             H                                       Cl       i-Pr        H                H                                       Cl       c-Pr        4-F              H                                       Cl       c-Pr        4-F              3-Me                                    Cl       c-Pr        4-Cl             H                                       Cl       c-Pr        H                H                                       Br       i-Pr        4-F              H                                       Br       i-Pr        4-F              3-Me                                    Br       i-Pr        4-Cl             H                                       Br       i-Pr        H                H                                       Br       c-Pr        4-F              H                                       Br       c-Pr        4-F              3-Me                                    Br       c-Pr        4-Cl             H                                       Br       c-Pr        H                H                                       3-CF.sub.3Ph                                                                           i-Pr        4-F              H                                       3-CF.sub.3Ph                                                                           i-Pr        4-F              3-Me                                    3-CF.sub.3Ph                                                                           i-Pr        4-Cl             H                                       3-CF.sub.3Ph                                                                           i-Pr        H                H                                       3-CF.sub.3Ph                                                                           c-Pr        4-F              H                                       3-CF.sub.3Ph                                                                           c-Pr        4-F              3-Me                                    3-CF.sub.3Ph                                                                           c-Pr        4-Cl             H                                       3-CF.sub.3Ph                                                                           c-Pr        H                H                                       4-c-PrPh i-Pr        4-F              H                                       4-c-PrPh i-Pr        4-F              3-Me                                    4-c-PrPh i-Pr        4-Cl             H                                       4-c-PrPh i-Pr        H                H                                       4-c-PrPh c-Pr        4-F              H                                       4-c-PrPh c-Pr        4-F              3-Me                                    4-c-PrPh c-Pr        4-Cl             H                                       4-c-PrPh c-Pr        H                H                                       2-furyl  i-Pr        4-F              H                                       2-furyl  i-Pr        4-F              3-Me                                    2-furyl  i-Pr        4-Cl             H                                       2-furyl  i-Pr        H                H                                       2-furyl  c-Pr        4-F              H                                       2-furyl  c-Pr        4-F              3-Me                                    2-furyl  c-Pr        4-Cl             H                                       2-furyl  c-Pr        H                H                                       2-thienyl                                                                              i-Pr        4-F              H                                       2-thienyl                                                                              1-Pr        4-F              3-Me                                    2-thienyl                                                                              1-Pr        4-Cl             H                                       2-thienyl                                                                              i-Pr        H                H                                       2-thienyl                                                                              c-Pr        4-F              H                                       2-thienyl                                                                              c-Pr        4-F              3-Me                                    2-thienyl                                                                              c-Pr        4-Cl             H                                       2-thienyl                                                                              c-Pr        H                H                                       2-pyrimidyl                                                                            i-Pr        4-F              H                                       2-pyrimidyl                                                                            i-Pr        4-F              3-Me                                    2-pyrinidyl                                                                            i-Pr        4-Cl             H                                       2-pyrimidyl                                                                            i-Pr        H                H                                       2-pyrimidyl                                                                            c-Pr        4-F              H                                       2-pyrimidyl                                                                            c-Pr        4-F              3-Me                                    2-pyrimidyl                                                                            c-Pr        4-Cl             H                                       2-pyrimidyl                                                                            c-Pr        H                H                                       PhO      i-Pr        4-F              H                                       PhO      i-Pr        4-F              3-Me                                    PhO      i-Pr        4-Cl             H                                       PhO      i-Pr        H                H                                       PhO      c-Pr        4-F              H                                       PhO      c-Pr        4-F              3-Me                                    PhO      c-Pr        4-Cl             H                                       PhO      c-Pr        H                H                                       N(Me).sub.2                                                                            i-Pr        4-F              H                                       N(Me).sub.2                                                                            i-Pr        4-F              3-Me                                    N(Me).sub.2                                                                            i-Pr        4-Cl             H                                       N(Me).sub.2                                                                            i-Pr        H                H                                       N(Me).sub.2                                                                            c-Pr        4-F              H                                       N(Me).sub.2                                                                            c-Pr        4-F              3-Me                                    N(Me).sub.2                                                                            c-Pr        4-Cl             H                                       N(Me).sub.2                                                                            c-Pr        H                H                                       2-Phenethyl                                                                            i-Pr        4-F              H                                       2-Phenethyl                                                                            i-Pr        4-F              3-Me                                    2-Phenethyl                                                                            i-Pr        4-Cl             H                                       2-Phenethyl                                                                            i-Pr        H                H                                       2-Phenethyl                                                                            c-Pr        4-F              H                                       2-Phenethyl                                                                            c-Pr        4-F              3-Me                                    2-Phenethyl                                                                            c-Pr        4-Cl             H                                       2-Phenethyl                                                                            c-Pr        H                H                                       α-naphthyl                                                                       i-Pr        4-F              H                                       α-naphthyl                                                                       i-Pr        4-F              3-Me                                    α-naphthyl                                                                       i-Pr        4-Cl             H                                       α-naphthyl                                                                       i-Pr        H                H                                       α-naphthyl                                                                       c-Pr        4-F              H                                       α-naphthyl                                                                       c-Pr        4-F              3-Me                                    α-naphthyl                                                                       c-Pr        4-Cl             H                                       α-naphthyl                                                                       c-Pr        H                H                                       Ph       i-Pr        4-c-Pr           H                                       Ph       c-Pr        4-c-Pr           H                                       Ph       i-Pr        4-MeO            H                                       Ph       c-Pr        4-MeO            H                                       Ph       i-Pr        4-N(Me).sub.2    H                                       Ph       c-Pr        4-N(Me).sub.2    H                                       Ph       i-Pr        3-CF.sub.3       H                                       Ph       c-Pr        3-CF.sub.3       H                                       Ph       i-Pr        4-Ph             H                                       Ph       c-Pr        4-Ph             H                                       Ph       i-Pr        4-OH             H                                       Ph       c-Pr        4-OH             H                                       Ph       i-Pr        4-OCH.sub.2 Ph   H                                       Ph       c-Pr        4-OCH.sub.2 Ph   H                                       Ph       i-Pr        4-OSiMe.sub.3    H                                       Ph       c-Pr        4-OSiMe.sub.3    H                                       Ph       i-Pr        4-CH.sub.2 OH    H                                       Ph       c-Pr        4-CH.sub.2 OH    H                                       Ph       i-Pr        4-OCH.sub.2 CH.sub.2 OMe                                                                       H                                       Ph       c-Pr        4-OCH.sub.2 CH.sub.2 OMe                                                                       H                                       Ph       i-Pr        3,4-OCH.sub.2 O                                          Ph       c-Pr        3,4-OCH.sub.2 O                                          Ph       i-Pr        3,4-CHCHCHCH                                             Ph       c-Pr        3,4-CHCHCHCH                                             Ph       Me          4-F              H                                       Ph       Me          4-F              3-Me                                    Ph       Me          4-Cl             H                                       Ph       Me          H                H                                       Ph       Et          4-F              H                                       Ph       Et          4-F              3-Me                                    Ph       Et          4-Cl             H                                       Ph       Et          H                H                                       Ph       n-Pr        4-F              H                                       Ph       n-Pr        4-F              3-Me                                    Ph       n-Pr        4-Cl             H                                       Ph       n-Pr        H                H                                       Ph       n-Hex       4-F              H                                       Ph       n-Hex       4-F              3-Me                                    Ph       n-Hex       4-Cl             H                                       Ph       n-Hex       H                H                                       Ph       C(CH.sub.2)CH.sub.2                                                                       4-F              H                                       Ph       C(CH.sub.2)CH.sub.2                                                                       4-F              3-Me                                    Ph       C(CH.sub.2)CH.sub.2                                                                       4-Cl             H                                       Ph       C(CH.sub.2)CH.sub.2                                                                       H                H                                       Ph       c-Hex       4-F              H                                       Ph       c-Hex       4-F              3-Me                                    Ph       c-Hex       4-Cl             H                                       Ph       c-Hex       H                H                                       Ph       3-c-Pentenyl                                                                              4-F              H                                       Ph       3-c-Pentenyl                                                                              4-F              3-Me                                    Ph       3-c-Pentenyl                                                                              4-Cl             H                                       Ph       3-c-Pentenyl                                                                              H                H                                       Ph       Ph          4-F              H                                       Ph       Ph          4-F              3-Me                                    Ph       Ph          4-Cl             H                                       Ph       Ph          H                H                                       Ph       CH.sub.2 Ph 4-F              H                                       Ph       CH.sub.2 Ph 4-F              3-Me                                    Ph       CH.sub.2 Ph 4-Cl             H                                       Ph       CH.sub.2 Ph H                H                                       ______________________________________                                    

Further, pharmaceutically acceptable salts such as potassium salts, 1/2calcium salts, esters such as methyl ester, n propyl ester, i-propylester, c-propyl ester, n-butyl ester, i-butyl ester, sec-butyl ester,t-butyl ester, n-pentyl ester, i-pentyl ester and n-hexyl ester, orammonium salts or trimethylamine salts of these compounds can beprepared in the same manner.

The compounds of the present invention exhibit high inhibitoryactivities against the cholesterol biosynthesis wherein HMG-CoAreductase acts as a rate limiting enzyme, as shown by the test resultsgiven hereinafter, and thus are capable of suppressing or reducing theamount of cholesterol in blood as lipoprotein. Thus, the compounds ofthe present invention are useful as curing agents againsthyperlipidemia, hyperlipoproteinemia and atheroscleosis.

They may be formulated into various suitable formulations depending uponthe manner of the administration. The compounds of the present inventionmay be administered in the form of free acids or in the form ofphysiologically hydrolyzable and acceptable esters or lactones, orpharmaceutically acceptable salts.

The pharmaceutical composition of the present invention is preferablyadministered orally in the form of the compound of the present inventionby itself or in the form of powders, granules, tablets or capsulesformulated by mixing the compound of the present invention with asuitable pharmaceutically acceptable carrier including a binder such ashydroxypropyl cellulose, syrup, gum arabic, gelatin, sorbitol,tragacanth gum, polyvinyl pyrrolidone or CMC-Ca, an excipient such aslactose, sugar, corn starch, calcium phosphate, sorbitol, glycine orcrystal cellulose powder, a lubricant such as magnesium stearate, talc,polyethylene glycol or silica, and a disintegrator such as potatostarch.

However, the pharmaceutical composition of the present invention is notlimited to such oral administration and it is applicable for parenteraladministration. For example, it may be administered in the form of e.g.a suppository formulated by using oily base material such as cacaobutter, polyethylene glycol, lanolin or fatty acid triglyceride, atransdermal therapeutic base formulated by using liquid paraffin, whitevaseline, a higher alcohol, Macrogol ointment, hydrophilic ointment orhydro-gel base material, an injection formulation formulated by usingone or more materials selected from the group consisting of polyethyleneglycol, hydro-gel base material, distilled water, distilled water forinjection and an excipient such as lactose or corn starch, or aformulation for administration through mucous memberanes such as anocular mucous membrane, a nasal mucous membrane and an oral mucousmembrane.

Further, the compounds of the present invention may be combined withbasic ion-exchange resins which are capable of binding bile acids andyet not being absorbed by the gastrointestinal tract.

The daily dose of the compound is from 0.05 to 500 mg, preferably from0.5 to 50 mg, for an adult. It is administered from once to three timesper day. The dose may of course be varied depending upon the age, theweight or the condition of illness of the patient.

The compounds of the formulas II to X are novel, and they are importantintermediates for the preparation of the compounds of the formula I.Accordingly, the present invention relates also to the compounds of theformulas II to X and the processes for their production.

Now, the present invention will be described in further detail withreference to Test Examples for the pharmacological activities of thecompounds of the present invention, their Preparation Examples andformulation Examples. However, it should be understood that the presentinvention is by no means restricted by such specific Examples.

PHARMACOLOGICAL TEST EXAMPLES Test A: Inhibition of cholesterolbiosynthesis from acetate in vitro

Enzyme solution was prepared from liver of male Wistar rat billialyconnulated and discharged bile for over 24 hours. Liver was cut out atmid-dark and microsome and supernatant fraction which was precipitablewith 40-80% of solution of ammonium sulfate (sup fraction) were preparedfrom liver homogenate according to the modified method of Knauss et.al.; Kuroda, M., et. al., Biochim. Biophys. Acta, 489, 119 (1977). Forassay of cholesterol biosynthesis, microsome (0.1 mg protein) and supfraction (1.0 mg protein) were incubated for 2 hours at 37° C. in 200 μlof the reaction mixture containing ATP; 1 mM, Glutathione; 6 mM,Glucose-1phosphate; 10 mM, AND; 0.25 mM, NADP; 0.25 mM, CoA; 0.04 mM and0.2 mM [2-14C]sodium acetate (0.2 μCi) with 4 μl of test compoundsolution dissolved in water or dimethyl sulfoxide. To stop reaction andsaponify, 1 ml of 15% EtOH-KOH was added to the reactions and heated at75° C. for 1 hour. Nonsaponifiable lipids were extracted with petroleumether and incorporated ¹⁴ C radioactivity was counted. Inhibitoryactivity of compounds was indicated with IC50.

Test B: Inhibition of cholesterol biosynthesis in culture cells

Hep G2 cells at over 5th passage were seeded to 12 well plates andincubated with Dulbecco's modified Eagle (DME) medium containing 10% offetal bovine serum (FBS) at 37° C., 5% CO₂ until cells were confluentfor about 7 days. Cells were exposed to the DME medium containing 5% oflipoprotein deficient serum (LpDS) prepared by ultracentrifugationmethod for over 24 hours. Medium was changed to 0.5 ml of fresh 5% LpDScontaining DME before assay and 10 μl of test compound solutiondissolved in water or DMSO were added. 0.2 μCi of [2-¹⁴ C]sodium acetate(20 μl) was added at 0 hr(B-1) or 4 hrs(B-2) after addition ofcompounds. After 4 hrs further incubation with [2-¹⁴ C] sodium acetate,medium was removed and cells were washed with phosphate buffered saline(PBS) chilled at 4° C. Cells were scraped with rubber policeman andcollected to tubes with PBS and digested with 0.2 ml of 0.5 N KOH at 37°C. Aliquot of digestion was used for protein analysis and remaining wassaponified with 1 ml of 15% EtOH-KOH at 75° C. for 1 hour.Nonsaponifiable lipids were extracted with petroleum ether and ¹⁴ Cradioactivity was counted. Counts were revised by cell protein andindicated with DPM/mg protein. Inhibitory activity of compounds wasindicated with IC50.

Test C: Inhibition of cholesterol biosynthesis in vivo

Male Sprague-Dawley rats weighing about 150 g were fed normal Purinachow diet and water ad libitum, and exposed to 12 hours light/12 hoursdark lighting pattern

(2:00 PM -2:00 AM dark) prior to use for in vivo inhibition test ofcholesterol biosynthesis. Animals were separated groups consisting offive rats as to be average mean body weight in each groups. Testcompounds at dosage of 0.02-2.0 mg/kg body weight (0.4 ml/100 g bodyweight), were dissolved in water or suspended in 0.5% methyl celluloseand orally administered at 2-3 hours before mid-dark (8:00 PM), whilecholesterol biosynthesis reaches to maximum in rats. As control, ratswere orally administered only water or vehicle. At 90 minutes aftersample administration, rats were injected intraperitoneally with 10 μCiof [2-¹⁴ C]sodium acetate at volume of 0.2 ml per one. 2 Hours later,blood samples were obtained and serum were separated immediately. Totallipids were extracted according to the method of Folch et al. andsaponified with EtOH-KOH. Nonsaponifiable lipids were extracted withpetroleum ether and radio activity incorporated into nonsaponifiablelipids was counted.

Inhibitory activity was indicated as percent decrease of counts intesting groups (DPM/2 ml serum/2 hours) from that in control group.

With respect to the compounds of the present invention, the inhibitoryactivities against the cholesterol biosynthesis in which HMG-CoAreductase serves as a rate limiting enzyme, were measured by the aboveTest A and B. The results are shown in Tables 2 and 3.

The chemical structure of Reference Compound is shown as follows.##STR32##

IC₅₀ of CS-514 in Test A was 9.0×10⁻⁹ M/l.

The relative activities of the compounds of the present invention basedon the activities of CS-514 by Test A being evaluated to be 1, are shownin Table 2.

                  TABLE 2                                                         ______________________________________                                        Relative activities by Test A                                                 Compound of                                                                   the present invention                                                                          Relative activities                                          ______________________________________                                        I-1-1            1.6                                                          I-5-1            1.3                                                          I-5-2            0.6                                                          ______________________________________                                    

In Table 3, the inhibition activities of the test compounds at aconcentration of 100×10⁻⁹ M/l, are shown.

                  TABLE 3                                                         ______________________________________                                        Inhibition activities by Test B-1                                             Compound of                                                                   the present invention                                                                         Inhibition activities                                         ______________________________________                                        (Reference compound)                                                          CS-514          18.4                                                          (Compound of                                                                  the present invention)                                                        I-1-1           50.1                                                          I-1-2           57.3                                                          I-5-2           43.2                                                          II-1            52.6                                                          ______________________________________                                    

Results of the measurement of the inhibitory activities by Test C

The percent decreases of counts after the oral administration of 0.2mg/kg of compound I-5-2 was 34.3%, relative to the measured value of thecontrol group. The percent decrease of counts after the oraladministration of 0.2 mg/kg of CS-514 was 34% under the same condition.

As is evident from the foregoing, the compounds of the present inventionexhibited activities equivalent or superior to the reference compoundCS-514 in Tests A, B-1 and C.

Test D: Acute toxicity

A 0.5% CMC suspension of a test compound was orally administered to ICRmale mice (group of three mice). The acute toxicity was determined basedon the mortality after seven days. With compound I-5-2 of the presentinvention, only one animal of the three animals died.

EXAMPLE 1 Ethyl (E)7-[4'-(4"-fluorophenyl)-3'-methyl-6'-(1"-methylethyl)isoxazolo[[5,4-b]pyridin-5'-yl]-3,5-dihydroxyhept-6-enoate(Compound I-1-1)

This compound was prepared by the synthesis comprising the followingreaction steps Example 1-a_(o) to Example 1-f.

EXAMPLE a_(o) -1 Ethyl4-(4'-fluorophenyl)-3-methyl-6-(1'-methylethyl)-4,7-dihydroisoxazolo[5,4-b]pyridin-5-ylcarboxylate (Compound X-1)

This compound was prepared in accordance with the method disclosed inJapanese Unexamined Patent Publication No. 152386/1984.

4.90 g (5×10⁻² of 5-amino-3-methylisoxazole (Compound XI-1) and 13.20 g(5×10⁻² mol) of ethyl 2(4'-fluorobenzylidene)-4-methyl-3-oxopentanoate(Compound XII-1) were dissolved in tert-butyl alcohol, and the solutionwas heated at 80° C. for about day and night. After confirming thecomplete disappearance of the starting materials by thin layerchromatography, the solvent was distilled off under reduced pressurefrom the reaction solution by an evaporator. The residual oil wassubjected to silica gel column chromatography (eluent: benzene/ethylacetate) to obtain 5.57 g (yield: 32.4%) of the desired compound asslightly yellow oily substance.

EXAMPLE a_(o) -2 Ethyl4(4'-fluorophenyl)-3-methyl-6-(1'-methylethyl]isoxazolo[5,4-b]pyridin-5-ylcarboxylate(Compound VII-1)

9.00 g (2.62×10⁻² mol) of Compound X-1 was dissolved in 100 ml ofacetone dehydrated by Molecular Sieves, and 6.21 g of potassiumpermanganate was added thereto. The mixture was stirred at roomtemperature.

Four hours later, the disappearance of the starting material wascofirmed by thin layer chromatography, and then, the reaction mixturewas subjected to filtration to remove insolubles. The solvent wasdistilled off under reduced pressure from the filtrate by an evaporator.The residual solid was dissolved benzene, and the solution was subjectedto activated carbon treatment. Then, the solvent was distilled off toobtain 6.55 g (73.1 %) of the desired compound as brown powder.

Melting point: 95°-102° C.4-(4'-fluorophenyl-5-hydroxymethyl-3-methyl-6-(1'methylethyl)isoxazolo[5,4-b]pyridine(Compound VI-1)

6.55 g (1.92×10⁻² mol) of Compound VII-1 was dissolved in 100 ml oftoluene dehydrated by Molecular Sieves, and the solution was cooled to-b 10° C. under a nitrogen atmosphere and stirred.

To this solution, 57.6 ml of a 16 weight % dibutylaluminumhydride-toluene solution was gradually dropwise added, and the mixturewas stirred at -10° C. for 2.5 hours.

After confirming the disappearance of the starting material by thinlayer chromatography, 100 ml of diethyl ether was added to the reactionsolution, and cold and diluted hydrochloric acid was carefully dropwiseadded thereto to terminate the reaction. The ether layer was separated,washed twice with a saturated sodium chloride aqueous solution, thendried over anhydrous magnesium sulfate and subjected to filtration. Thesolvent was distilled off by an evaporator and a vacuum pump, and theresidual solid was subjected to silica gel column chromatography(eluent: benzene/ethyl acetate) to obtain 2.27 g (yield: 39.4%) of thedesired compound as slightly yellow powder.

Melting point: 90°-110° C.

EXAMPLE 1-b4-(4'-fluorophenyl)-3-methyl-6-(1'-methylethyl)-isoxazolo[5,4-b]pyridin-5-ylcarboxyaldehyde(Compound V-1)

2.27 g (7.57×10⁻³ mol) of Compound VI-1 was dissolved in 20 ml ofdichloromethane dehydrated by Molecular Sieves, and 0.15 g of anhydroussodium acetate was added thereto to prepare a suspension. 1.89 g(8.77×10⁻³ mol) of powder of pyridinium chlorochromate was graduallyadded to the suspension under cooling with ice and stirring, and themixture was stirred at room temperature for about 11 hours. Afterconfirming the disappearance of the starting materials by thin layerchromatography, 100 ml of diethyl ether was added thereto, and themixture was stirred.

The reaction mixture was subjected to suction filtration through asilica gel layer. The residual tar was sufficiently washed with diethylether until the tar became powder. The washing solution was subjected tofiltration through the silica gel layer and put together with theabove-mentioned filtrate. The solvent was evaporated by an evaporator.The residue was dissolved in benzene, and the benzene solution wassubjected to activated carbon treatment. The crude crystal obtained bydistillation of the solvent, was subjected to silica gel columnchromatography (eluent: benzene/ethyl acetate) to obtain 1.75 g (yield:77.6%) of the desired compound as slightly yellow powder.

Melting point: 76°-81° C.

EXAMPLE 1-c-(3'-ethoxy-1'-hydroxy-2'-propen-1'-yl)-4-(4'-fluorophenyl)-3-methyl-6-(1'-methylethyl)isoxazolo[5,4b]pyridine(Compound IV-1)

4.23 g (11.7 mmol) of cis-1-ethoxy-2-(tri-n-butylstannyl)ethylene wasdissolved in 120 ml of dry tetrahydrofuran, and the solution was cooledto -78° C. under a nitrogen atmosphere. 7.97 ml (12.9 mmol) of a 15weight % n-butyl lithium-n-hexane solution was dropwise added to thissolution. The mixture was stirred for 20 minutes, and then, a solutionof 1.75 g (5.87 mmol) of Compound V-1 dissolved in 120 ml of drytetrahydrofuran was dropwise added thereto. The reaction mixture wasstirred at -78° C. for 1.5 hours, and then, 5 ml of a saturated ammoniumchloride solution was added thereto to terminate the reaction. Theorganic layer was extracted with diethyl ether. The ether extract waswashed with a saturated sodium chloride aqueous solution and dried overanhydrous magensium sulfate. The solvent was distilled off under reducedpressure, and the residue was subjected to liquid separation betweenn-hexane and acetonitrile. The acetonitrile layer was subjected todistillation under reduced pressure to obtain the desired compound asslightly yellow powder. Melting point: 35°-40° C.

EXAMPLE 1-d(E)-3-[4'-(4"-fluorophenyl)-3'-methyl-6'-(1"-methylethy)isoxazolo[5,4-b]pyridin-5'-yl]-2-propenal(Compound III-1)

1.96 g of Compound IV-1 was dissolved in 40 ml of tetrahydrofuran, and10 ml of water and 50 mg of p-toluenesulfonic acid were added thereto.The mixture was stirred at room temperature for 3 hours. Diethyl etherwas added to the reaction solution, and the extraction was conducted afew times. The extract was washed with a saturated sodium chlorideaqueous solution and dried over anhydrous magnesium sulfate. Then, thesolvent was distilled off under reduced pressure. The residue wassubjected to silica gel column chromatography (eluent: 50% ethylacetate/benzene) to obtain the desired compound as slightly yellowpowder.

Melting point: 127°-129° C.

EXAMPLE 1-e Ethyl(E)-7-[4'-(4"-fluorophenyl)-3'-methyl-6'-(1"-methylethyl)isoxazolo[-5,4-b]pyridin-5-yl]-5'-hydroxy-3-oxohepto-6-enoate(Compound II-1)

0.25 g of 55 wt % sodium hydride was washed with dry hexane, dried undera nitrogen stream and then suspended in 65 ml of dry tetrahydrofuran.The suspension was stirred to -15° C. under a nitrogen atmosphere, and0.71 g (5.46×10⁻³ mol) of ethyl acetoacetate was gradually dropwiseadded thereto. The mixture was stirred at -15° C. for 20 minutes. Then,3.33 ml (5.39×10⁻³ mol) of a 1.62 M/l n-butyl lithium-n-hexane solutionwas dropwise added thereto, and the mixture was stirred for 20 minutes.Further, a solution of 1.04 g (3.21×10⁻³ mol) of Compound III-1dissolved in 25 ml of dry tetrahydrofuran was dropwise added thereto,and the mixture was stirred for 5 hours. A cold saturated ammoniumchloride aqueous solution was added to the reaction mixture, and themixture was extracted with diethyl ether. The ether layer was washedwith a saturated sodium chloride aqueous solution, dried over anhydrousmagnesium sulfate and then subjected to filtration. The solvent wasevaporated by an evaporator. The residue was subjected to silica gelcolumn chromatography (eluent: benzene/ethyl acetate) to obtain 0.57 g(yield: 39.1%) of the desired compound as slightly brown powder.

Melting point: 104°-110° C.

EXAMPLE 1-f Ethyl(E)-7-4'-(4"-fluorophenyl)-3'-methyl-6'-(1"methylethyl)isoxazolo[5,4-b]pyridin-5'-yl]-3,5-dihydroxyhept-6-enoate(Compound I-1-1)

20 ml (about 3×10⁻³ mol) of a diethyl ether solution of about 0.15 mol/lof zinc borohydride was cooled to -70° C. under a nitrogen atmosphere. Asolution of 295 mg (6.5×10⁻⁴ mol) of Compound II-1 dissolved in 40 ml ofdry diethyl ether was gradually added thereto. Further, the reactionsolution was stirred at -70° C. for 2 hours. After confirming thedisappearance of the starting material II-1 by thin layerchromatography, 3 ml of methanol and then 10 ml of water was addedthereto at -70° C. to terminate the reaction. Further, 120 ml of waterand 120 ml of diethyl ether was added thereto and a diluted acetic acidaqueous solution was added thereto to adjust pH to 4, and the productwas extracted with diethyl ether.

The diethyl ether layer was washed with water and with a saturatedsodium chloride aqueous solution. The diethyl ether layer was dried overanhydrous magnesium sulfate, and then, the solvent was evaporated by anevaporator. The residual oil was subjected to silica gel columnchromatography (eluent: benzene/ethyl acetate) to obtain 140 mg (yield:47.3%) of the desired compound as slightly yellow powder

Melting point: 98°-104° C.

MS (m/e, FAB): 457(M+H).

NMR (in CDCl₃) δppm: 1.29(t,3H,J=7 Hz), 1.33(d,6H,J=7 Hz),1.3-1.5(m,2H), 1.97(s,3H), 2.3-2.5(m,2H), 3.2-3.8(m,2H),3.47(Heptalet,1H,J=7 Hz), 4.19(q,2H,J=7 Hz), 4.0-4.5(m,2H),5.34(dd,1H,J=6 Hz,17 Hz), 6.52(d,1H,J=17 Hz), 7.1-7.4(m,4H).

EXAMPLE 2 Sodium(E)-7-[4'-(4"-fluorophenyl)-3'-methyl-6'-(1"-methylethyl)isoxazolo[5,4-b]pyridin-5'-yl]-3,5-dihydroxyhept-6-enoate(Compound I-5-1: sodium salt of Compound I-1-1)

89.6 mg (1.96×10⁻⁴ mol) of Compound I-1-1 was dissolved in 3 ml ofethanol, and 0.37 ml of a 0.5N sodium hydroxide aqueous solution wasdropwise added thereto. The mixture was stirred at room temperature for4 hours. Then, ethanol was distilled off under reduced pressure at 45°C., 5 ml of distilled water was added thereto, and the residual startingmaterial was extracted with diethyl ether. The aqueous layer wasfreeze-dried to obtain 88.2 mg (yield: 100%) of hygroscopic slightlyyellow powder.

Melting point: 125°-130° C.

MS (m/e, FAB): 473(M+Na), 451(M+H), 329.

NMR (in d₆ -DMSO) δppm: 1.09-1.5(m,2H), 1.26(d,6H,J=7 Hz), 1.89(s,3H),1.6-2.1(m,2H), 2.9-3.8(m,3H), 3.52(Heptalet,1H,J=7 Hz), 3.9-4.3(m,1H),5.40(dd,1H,J=6 Hz,17 Hz), 6.38(d,1H,J=17 Hz), 7.1-7.5(m,4H).

In the same manner as in Example 1-a₀ (a₀ -1˜a₀ -2), Compound VII-2 wasprepared.

                  TABLE 4                                                         ______________________________________                                         ##STR33##                                                                                                           Melting                                Compound                                                                              R.sup.1                                                                             R.sup.2  R.sup.3                                                                            R.sup.4                                                                             R.sup.21                                                                           point (°C.)                     ______________________________________                                        VII-2   Ph    i-Pr     4-F  H     Et   104-106                                ______________________________________                                    

In the same manner as in Example 1-a, Compound VI-2 was prepared.

                  TABLE 5                                                         ______________________________________                                         ##STR34##                                                                                                        Melting                                   Compound  R.sup.1 R.sup.2                                                                              R.sup.3                                                                              R.sup.4                                                                           point (°C.)                        ______________________________________                                        VI-2      Ph      i-Pr   4-F    H   140-150                                   ______________________________________                                    

In the same manner as in Example 1-b, Compound V-2 was prepared.

                  TABLE 6                                                         ______________________________________                                         ##STR35##                                                                                                        Melting                                   Compound  R.sup.1 R.sup.2                                                                              R.sup.3                                                                              R.sup.4                                                                           point (°C.)                        ______________________________________                                        V-2       Ph      i-Pr   4-F    H   141-149                                   ______________________________________                                    

In the same manner as in Example 1-c, Compound IV-2 was prepared.

                  TABLE 7                                                         ______________________________________                                         ##STR36##                                                                                                        Melting                                   Compound  R.sup.1 R.sup.2                                                                              R.sup.3                                                                              R.sup.4                                                                           point (°C.)                        ______________________________________                                        IV-2      Ph      i-Pr   4-F    H   42-47                                     ______________________________________                                    

In the same manner as in Example 1-d, Compound III-2 was prepared.

                  TABLE 8                                                         ______________________________________                                         ##STR37##                                                                                                        Melting                                   Compound  R.sup.1 R.sup.2                                                                              R.sup.3                                                                              R.sup.4                                                                           point (°C.)                        ______________________________________                                        III-2     Ph      i-Pr   4-F    H   185-186.5                                 ______________________________________                                    

In the same manner as in Example 1-e, Compound II-2 was prepared.

                  TABLE 9                                                         ______________________________________                                         ##STR38##                                                                                                           Melting                                Compound                                                                              R.sup.1                                                                             R.sup.2  R.sup.3                                                                            R.sup.4                                                                             R.sup.12                                                                           point (°C.)                     ______________________________________                                        II-2    Ph    i-Pr     4-F  H     Et   Oil                                    ______________________________________                                    

NMR (in CDCl₃) δppm: 1.30(t,3H,J=7 Hz), 1.35(d,6H,J=7 Hz),2.4-2.7(m,2H), 3.2-3.8(m,2H), 3.45(s,2H), 4.20(q,2H,J=7 Hz),4.4-4.9(m,1H), 5.43(dd,1H,J=17 Hz), 6.70(d,1H,J=17 Hz), 6.7-7.5(m,9H).

In the same manner as in Example 1-f, Compound I-1-2 was prepared.

                  TABLE 10                                                        ______________________________________                                         ##STR39##                                                                                                           Melting                                Compound                                                                              R.sup.1                                                                             R.sup.2  R.sup.3                                                                            R.sup.4                                                                             R.sup.12                                                                           point (°C.)                     ______________________________________                                        I-1-2   Ph    i-Pr     4-F  H     Et   100-103                                ______________________________________                                    

MS (m/e): 518, 516, 482, 357.

NMR (in CDCl₃) δppm: 1.28(t,3H,J=7 Hz), 1.37(d,6H,J=7 Hz),1.2-1.5(m,2H), 2.3-2.5(m,2H), 2.6-3.1(m,2H), 3.52(Heptalet,1H,J=7 Hz),4.18(q,2H,J=7 Hz), 3.9-4.5(m,2H), 5.28(dd,1H,J=6 Hz,17 Hz),6.57(d,1H,J=17 Hz), 6.7-7.5(m,9H).

In the same manner as in Example 2, Compound I-5-2 was prepared.

                  TABLE 11                                                        ______________________________________                                         ##STR40##                                                                                                           Melting                                Compound                                                                              R.sup.1                                                                             R.sup.2  R.sup.3                                                                            R.sup.4                                                                             R.sup.12                                                                           point (°C.)                     ______________________________________                                        I-5-2   Ph    i-Pr     4-F  H     Na   123-125                                ______________________________________                                    

MS (m/e, FAB): 535(M+Na), 513(M+H), 414.

NMR (in d₆ -DMSO) δppm: 0.8-1.3(m,2H), 1.30(d,6H,J=7 Hz), 1.7-2.(m,3H),3.1-3.8(m,3H), 3.9-4.3(m,1H), 5.36(dd,1H,J=6 Hz,17 Hz), 6.42(d,1H,J=17Hz), 6.6-7.5(m,9H).

FORMULATION EXAMPLE 1

    ______________________________________                                        Tablets                                                                       ______________________________________                                        Compound I-5-1          1.0 g                                                 Lactose                 5.0 g                                                 Crystal cellulose powder                                                                              8.0 g                                                 Corn starch             3.0 g                                                 Hydroxypropyl cellulose 1.0 g                                                 CMC-Ca                  1.5 g                                                 Magnesium stearate      0.5 g                                                 Total                   20.0 g                                                ______________________________________                                    

The above components were mixed by a usual method and then tabletted toproduce 100 sugar coating tablets each containing 10 mg of the activeingredient.

FORMULATION EXAMPLE 2

    ______________________________________                                        Capsules                                                                      ______________________________________                                        Compound I-5-1          1.0 g                                                 Lactose                 3.5 g                                                 Crystal cellulose powder                                                                              10.0 g                                                Magnesium stearate      0.5 g                                                 Total                   15.0 g                                                ______________________________________                                    

The above components were mixed by a usual method and then packed in No.4 gelatin capsules to obtain 100 capsules each containing 10 mg of theactive ingredient.

FORMULATION EXAMPLE 3

    ______________________________________                                        Soft capsules                                                                 ______________________________________                                        Compound I-5-1           1.00 g                                               PEG (polyethylene glycol) 400                                                                          3.89 g                                               Saturated fatty acid triglyceride                                                                      15.00 g                                              Peppermint oil           0.01 g                                               Polysorbate 80           0.10 g                                               Total                    20.00 g                                              ______________________________________                                    

The above components were mixed and packed in No. 3 soft gelatincapsules by a usual method to obtain 100 soft capsules each containing10 mg of the active ingredient.

FORMULATION EXAMPLE 4

    ______________________________________                                        Ointment                                                                      ______________________________________                                        Compound I-5-1     1.0 g   (10.0 g)                                           Liquid Paraffin    10.0 g  (10.0 g)                                           Cetanol            20.0 g  (20.0 g)                                           White vaseline     68.4 g  (59.4 g)                                           Ethylparaben       0.1 g   (0.1 g)                                            l-menthol          0.5 g   (0.5 g)                                            Total              100.0 g                                                    ______________________________________                                    

The above components were mixed by a usual method to obtain a 1% (10%)ointment.

FORMULATION EXAMPLE 5

    ______________________________________                                        Suppository                                                                   ______________________________________                                        Compound I-5-1         1.0 g                                                  Witepsol H15*          46.9 g                                                 Witepsol W35*          52.0 g                                                 Polysorbate 80         0.1 g                                                  Total                  100.0 g                                                ______________________________________                                         *Trademark for triglyceride compound                                     

The above components were melt-mixed by a usual method and poured intosuppository containers, followed by cooling for solidification to obtain100 suppositories of 1 g each containing 10 mg of the active ingredient.

FORMULATION EXAMPLE 6 Injection formulation

Compound I-5-1 1 mg

Distilled water for injection formulation 5 ml

The formulation is prepared by dissolving the compound in the distilledwater whenever it is required.

FORMULATION EXAMPLE 7

    ______________________________________                                        Granules                                                                      ______________________________________                                        Compound I-5-1          1.0 g                                                 Lactose                 6.0 g                                                 Crystal cellulose powder                                                                              6.5 g                                                 Corn starch             5.0 g                                                 Hydroxypropyl cellulose 1.0 g                                                 Magnesium stearate      0.5 g                                                 Total                   20.0 g                                                ______________________________________                                    

The above components were granulated by a usual method and packaged toobtain 100 packages each containing 200 mg of the granules so that eachpackage contains 10 mg of the active ingredient.

We claim:
 1. The compound of the formula: ##STR41## wherein R¹ ishydrogen, C₁₋₈ alkyl, C₂₋₆ alkenyl, C₃₋₇ cycloalkyl, C₁₋₆ alkoxy, C₁₋₆alkylthio, fluoro, chloro, bromo, ##STR42## (wherein R⁵, R⁶ and R⁷ areindependently hydrogen, C₁₋₄ alkyl, C₁₋₃ alkoxy, C₃₋₇ cycloalkyl,trifluoromethyl, fluoro, chloro or bromo), 2-, 3- or 4-pyridyl, 2- or3-thienyl, 2- or 3-furyl, 2- or 5-pyrimidyl, ##STR43## (wherein R⁵ is asdefined above) or --NR⁸ R⁹ (wherein R⁸ and R⁹ are independentlyhydrogen, C₁₋₄ alkyl or ##STR44## (wherein R⁵ is as defined above, and mis 1, 2 or 3) or R⁸ and R⁹ together form --(CH₂)_(j) -- (wherein j is 3,4 or 5)); or C₁₋₃ alkyl substituted by ##STR45## (wherein R⁵ is asdefined above) and by 0, 1 or 2 members selected from the groupconsisting of C₁₋₈ alkyl, or α- or β-naphthyl; R² is hydrogen, C¹⁻⁸alkyl, C₂₋₆ alkenyl, C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl or ##STR46##(wherein R⁵ is as defined above), or C₁₋₃ alkyl substituted by ##STR47##(wherein R⁵, R⁶ and R⁷ are as defined above) and by 0, 1 or 2 membersselected from the group consisting of C₁₋₃ alkyl; R³ and Rhu 4 areindependently hydrogen, C₁₋₈ alkyl, C₃₋₇ cycloalkyl, C₁₋₃ alkoxy,n-butoxy, i-butoxy, sec-butoxy, t-butoxy, R²³ R²⁴ N--- (R²³ and R²⁴ areindependently hydrogen or C₁₋₃ alkyl), trifluoromethyl,trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, phenyl,phenoxy, benzyloxy, hydroxy, trimethylsilyloxy,diphenyl-t-butylsilyloxy, hydroxymethyl or --O(CH₂)_(l) OR¹⁰ (whereinR¹⁰ is hydrogen, or C₁₋₃ alkyl, and l is 1, 2 or 3); or when located atthe ortho position to each other, R³ and R⁴ may together form--CH═CH--CH═CH-- or methylenedioxy; Y is --CH₂ --, --CH₂ CH2--,--CH═CH--, --CH₂ --CH═CH--, --CH═CH--CH₂ --, --C(CH₃)═CH-- or--CH═C(CH₃)--; and Z is --Q--CH₂ WCH₂ --CO₂ R¹², ##STR48## (wherein Q is--C(O)--, --C(OR¹³)₂ -- or --CH(OH)--; W is --C(O)--, --C(OR¹³)₂ or--C(R¹¹)(OH)--; R¹¹ is hydrogen or C₁₋₃ alkyl; R¹² is hydrogen, R¹⁴(wherein R¹⁴ is alkyl moiety of chemically or physiologicallyhydrolyzable alkyl ester) or M (wherein M is NHR¹⁷ R¹⁸ R¹⁹ (wherein R¹⁷,R¹⁸ and R¹⁹ are independently hydrogen or C₁₋₄ alkyl), sodium, potassiumor 1/2 calcium); two R¹³ are independently primary or secondary C₁₋₆alkyl; or two R₁₃ together form --(CH₂)₂ -- or --(CH₂)₃ --; and R¹⁵ andR¹⁶ are independently hydrogen or C₁₋₃ alkyl; or R¹⁵ and R¹⁶ togetherform --(CH₂)₂ -- or --(CH₂)₃ --).
 2. The compound according to claim 1,wherein in the formula I, R¹ is hydrogen, C₁₋₈ alkyl, C₂₋₆ alkenyl, C₃₋₇cycloalkyl, C₁₋₆ alkoxy, fluoro, chloro, bromo, ##STR49## (wherein R⁵,R⁶ and R⁷ are independently hydrogen, C₁₋₄ alkyl, C₁₋₃ alkoxy, C₃₋₇cycloalkyl, trifluoromethyl, fluoro, chloro or bromo), 2-, 3- or4-pyridyl, 2- or 3-thienyl, 2- or 3-furyl, 2- or 5-pyrimidyl or##STR50## (wherein R⁵ is as defined above), or C₁₋₃ alkyl substituted by##STR51## (wherein R⁵ is as defined above) and by 0, 1 or 2 membersselected from the group consisting of C₁₋₈ alkyl, or α-or β-naphthyl; R²is hydrogen, C₁₋₈ alkyl, C₂₋₆ alkenyl, C₃₋₇ cycloalkyl; R³ and R⁴ areindependently hydrogen, C₁₋₈ alkyl, C₁₋₃ alkoxy, n-butoxy, i-butoxy,sec-butoxy, t-butoxy, trifluoromethyl, fluoro, chloro, bromo, phenoxy,benzyloxy, hydroxy, trimethylsilyloxy, diphenyl-t-butylsilyloxy,hydroxymethyl or --O(CH₂)_(l) OR¹⁰ (wherein R¹⁰ is hydrogen, or C₁₋₃alkyl, and l is 1, 2 or 3); or when located at the ortho position toeach other, R³ and R⁴ may together form methylenedioxy; Y is --CH₂ CH₂-- or --CH═CH--; and Z is --Q--CH₂ WCH₂ --CO₂ R¹², ##STR52## (wherein Qis --C(O)-- or --CH(OH)--; W is --C(O)-- or --C(OH)--; and R¹² is asdefined in claim 1).
 3. The compound according to claim 1, wherein inthe formula I, R¹ is hydrogen, C₁₋₈ alkyl, C₂₋₆ alkenyl, C₃₋₇cycloalkyl, ##STR53## (wherein R⁵, R⁶ and R⁷ are independently hydrogen,C₁₋₄ alkyl, C₁₋₃ alkoxy, C₃₋₇ cycloalkyl, trifluoromethyl, fluoro,chloro or bromo), 2-, 3- or 4-pyridyl, 2- or 3-thienyl, 2- or 3-furyl,or 2- or 5-pyrimidyl; or C₁₋₃ alkyl substituted by ##STR54## (wherein R⁵is as defined above) and by 0, 1 or 2 members selected from the groupconsisting of C₁₋₈ alkyl, or α-or β-naphthyl; R² is primary or secondaryC₁₋₄ alkyl or C₃₋₆ cycloalkyl; R³ and R⁴ are as defined in claim 2 andlocated at the 3- and 4-position; Y is --CH₂ CH₂ -- or (E)CH═CH--; and Zis as defined in claim
 2. 4. The compound according to claim 1, whereinin the formula I, R¹ is hydrogen, C₁₋₈ alkyl, C₂₋₆ alkenyl, C₃₋₇cycloalkyl, ##STR55## (wherein R⁵, R⁶ and R⁷ are independently hydrogen,C₁₋₄ alkyl, C₁₋₃ alkoxy, C₃₋₇ cycloalkyl, trifluoromethyl, fluoro,chloro or bromo); or C₁₋₃ alkyl substituted by ##STR56## (wherein R⁵ iaas defined above) and by 0, 1 or 2 members selected from the groupconsisting of C₁₋₈ alkyl; R² is ethyl, n-propyl, i-propyl orcyclopropyl; R³ and R⁴ are independently hydrogen, C₁₋₈ alkyl, fluoro,chloro or bromo, and they are located at the 3- and 4-position; and Yand Z are as defined in claim
 3. 5. The compound according to claim 1,wherein in the formula I, R¹ is hydrogen, methyl, ethyl, n-propyl,i-propyl, n-butyl, sec-butyl, i-butyl, t-butyl, n-hexyl, n-octyl, vinyl,isopropenyl, cyclopropyl, cyclohexyl, phenyl, 2-toluyl, 3-toluyl,4-toluyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl,3-trifluoromethylphenyl, 3,4-dichlorophenyl, 3,4-dimethylphenyl,3,4-dimethoxyphenyl, benzyl, α-methylbenzyl, 4-chlorobenzyl or4-methoxybenzyl; R² is i-propyl or cyclopropyl; when R⁴ is hydrogen, R³is hydrogen, 3-methyl, 4-methyl, 3-chloro, 4-chloro, 3-fluoro or4-fluoro; or R³ and R⁴ together form 3-methyl 4-chloro, 3,5-dichloro,3,5-difluoro, 3,5-dimethyl or 3-methyl-4-fluoro; and Y and Z are asdefined in claim
 3. 6. The compound according to claim 1, wherein in theformula I, R¹, R³, Y and Z are as defined in claim 1, and R² iscyclopropyl.
 7. The compound according to claim 1, which is(E)-7-[4'-(4"-fluorophenyl)-3'-methyl-6'-(1"-methylethyl)isoxazolo[5,4-b]pyridin-5'-yl]-3,5-dihydroxyhept-6-enoicacid, a sodium salt, methyl ester, ethyl ester, n-propyl ester ori-propyl ester of the carboxylic acid, or a lactone formed by thecondensation of the carboxylic acid with hydroxy at the 5-position. 8.The compound according to claim 1, which is(E)-7-[4'-(4"-fluorophenyl)-6'-(1"-methylethyl)-3'-phenylisoxazolo[5,4-b]pyridin-5'-yl]-3,5-dihydroxyhept-6-enoicacid, a sodium salt, methyl ester, ethyl ester, n-propyl ester ori-propyl ester of the carboxylic acid, or a lactone formed by thecondensation of the carboxylic acid with the hydroxy at the 5-position.9. An anti-hyperlipidemia agent containing the compound of the formula Ias defined in claim 1 mixed with a pharmaceutically acceptable carrier.10. An anti-hyperlipoproteinemia agent containing the compound of theformula I as defined in claim 1 mixed with a pharmaceutically acceptablecarrier.
 11. An anti-atherosclerosis agent containing the compound ofthe formula I as defined in claim 1 mixed with a pharmaceuticallyacceptable carrier.
 12. A method for reducing hyperlipidemia,hyperlipoproteinemia or atherosclerosis, which comprises administeringan effective amount of the compound of the formula I as defined in claim1.